CN1853728A - Method prescription and use for improving medicine or nutrient oral absorption - Google Patents

Method prescription and use for improving medicine or nutrient oral absorption Download PDF

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Publication number
CN1853728A
CN1853728A CNA2005100671261A CN200510067126A CN1853728A CN 1853728 A CN1853728 A CN 1853728A CN A2005100671261 A CNA2005100671261 A CN A2005100671261A CN 200510067126 A CN200510067126 A CN 200510067126A CN 1853728 A CN1853728 A CN 1853728A
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medicine
nutrient
preparation
oil
organic solvent
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祁东风
黄冬
贾韦国
孙平
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TIANBO BIOLOGICAL SCIENCE AND TECHNOLOGY Co Ltd SHANGHAI
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TIANBO BIOLOGICAL SCIENCE AND TECHNOLOGY Co Ltd SHANGHAI
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Priority to CNA2005100671261A priority Critical patent/CN1853728A/en
Priority to JP2008506904A priority patent/JP2008536879A/en
Priority to EP06722367A priority patent/EP1878445A4/en
Priority to PCT/CN2006/000718 priority patent/WO2006111085A1/en
Publication of CN1853728A publication Critical patent/CN1853728A/en
Priority to US11/875,047 priority patent/US20080038335A1/en
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Abstract

A method for increasing the absorptivity and the biologic utilization rate of the orally taken medicine or nutritive food features that said orally taken medicine or nutritive food is mixed with one or more organic solvent and then with one or more acid-resistant protectors. Its prescription and application are also disclosed.

Description

A kind of method, prescription and application thereof that improves medicine or nutrient oral absorption
Technical field
The present invention relates to a kind of method and composition prescription that changes oral drugs or nutraceutical absorption approach and improve whole bioavailability, be specifically related to medicinal or nutrition with having bioactive lipotropy, hydrophilic compounds or both mixture in the absorption of gastrointestinal system with improve medicine or method, composite formula and the application thereof of the whole bioavailability of nutrient.
Technical background
The oral administration mode of medicine and nutriment is the route of administration of the most frequently used and most convenient of medicine and nutriment, is absorbed into blood at the various absorption patterns of gastrointestinal by gastrointestinal system by medicine or nutrient.Yet, many medicines or the nutriment from natural product, developed, when its peroral dosage form of exploitation, because these drug molecules or nutraceutical lipotropy or hydrophilic attribute, their absorptions in gastrointestinal tract are subjected to it at the intravital metabolism mechanism of absorption of people, and the influence of the several factors in the human gastrointestinal tract absorption process, the influence factor comprises the physicochemical property of medicine itself, the dissolubility of medicine and dissolution velocity, the pH value of gastrointestinal tract diverse location, gastric emptying speed and wriggling, food and other contents in the gastrointestinal, bacterial species in the gastrointestinal tract and activity thereof etc.Be subjected to the influence of these factors, a part of medicine or nutriment are low in the intravital overall absorption rate of people, bioavailability is low, thereby have limited medicine or nutraceutical curative effect and effect.
Normally, oral drugs or nutraceutical absorption approach are at gastrointestinal tract, and mainly are at intestinal, and this is because medicine is short and absorption area is little in the stomach time of staying, and at intestinal time of staying intestinal and the intestinal wall absorption area is big.When by oral when entering digestive tract, medicine is disintegrate in stomach.Because gastric juice environmental factors, the for example influence of acid-base value, enzyme and cenobium, and medicine is in the time of staying of gastric short (being no more than 2 hours usually), situation such as make medicine that hydrolysis, enzymolysis take place in stomach or to separate out, medicine is difficult to be absorbed, and perhaps has only the fraction medicine to be absorbed.In this absorption process of medicine, the absorbing state of lipotropy and hydrophilic compound medicine is different.
Lipophilic compounds medicine or nutrient can be dissolved in lipid (oil) and some organic solvents, and the while is water insoluble basically or water solublity is very low.Lipophilic bioactive compound lacks solubility in aqueous medium be to limit a critical limitation factor of its therapeutic use, is difficult to give the patient effectively with this class medicine or nutrient.When the lipophilic medicine of this class or nutrient during with the form administration of the aqueous solution of fluid or some type and/or oil suspension or emulsifying agent, absorbance and bioavailability are also very low.This compounds is in the gastro-intestinal Fluid environment, and the meeting crystallization that influences that is subjected in the gastric juice acid and water is separated out, and the solids after separating out is can not be absorbed at the harmonization of the stomach intestinal.And the chemical compound of hydrophilic biologically active can water-soluble and most of organic solvents.This compounds is in above-mentioned gastro-intestinal Fluid environment, though can not separated out, be subjected to the effect of acid, water, plurality of enzymes and cenobium, can be at gastrointestinal tract generation hydrolysis and enzymolysis, therefore become its metabolite, thereby the ratio that finally is absorbed into the protype compound of blood can reduce also.Owing to finally be absorbed into most of composition of blood has not been oral preceding original shape medicine, thereby the pharmacologically active of original shape medicine also can't be achieved.
Especially like this by the medicinal or nutrition of extracting in the natural plants with the medicine or the nutrient of active component preparation.The medicinal active ingredient that extracts in natural plants has quite a few to belong to saponins, saponin is owing to have multiple medicinal and nutrition value, be widely used in preparing the medicine for the treatment of various diseases or be used for nutriment, as dammarane's saponins class medicine or nutrients such as ginsenoside, arasaponins.This compounds part is to belong to hydrophilic chemical compound, water miscible saponin is hydrolyzed (the pharmaceutical chemistry structure changes) running into gastric acid, continue hydrolysis or enzymolysis after entering intestinal, have only minimum part in intestinal, to be absorbed in the process intestinal cenobium metabolic process.Fat-soluble saponin metaclass then no matter in stomach or intestinal, runs into gastric juice or intestinal juice and all can crystallization separate out, and almost completely can not be absorbed.
For example, panoxadiol and triol type saponin (ginsenoside) all belong to hydrophilic chemical compound.The ginsenoside is the main effective ingredient in the Radix Ginseng, the ginsenoside is oral after the digestive tract absorption, absorbance is extremely low, for example, ginsenoside Rb1's absorbance only is 1%, and Rh2 is 3.4%, and Rg1 is 1.9% (Dong Shuhua etc., ginsenoside's internal metabolism repercussion study, 6 pages of " Radix Ginseng research " 2003 the 15th volumes first phase page 2 to the).For example according to bibliographical information (Wang Liping, ginsenoside's internal metabolism, 6 pages of " Strait Pharmaceutical Journal " 2000 the 12nd volumes the 4th phase page 4 to the), after giving the experimental mouse oral administration, the ginsenoside Rg1 is influenced by gastric acid, is broken down into C-20 (R) isomer of Rh1, Rh1 and the C-25 hydroxylation product of Rh1; And ginsenoside Rb1, Rb2 are broken down into the C-25 hydroxylation product of Rb1, Rb2 at gastric; The C-24 hydroxylation product of Rb1, Rb2; The C-25 peroxidating product of Rb1, Rb2; And the C-24 peroxidating product of Rb1, Rb2.And according to the research of Karikura etc. (Karikura et al., Chem.Pharm.Bull. (Tokyo) 1999.Feb, 39 (2): 400), at the gastric of experimental mouse, ginsenoside Rh2's hydrolysis seldom, the part that is decomposed obtains 4 kinds of metabolites: ginsenoside Rh2's 25-hydroxyl-23 alkene; 24-hydroxyl-25-alkene; 25-hydroperoxyl-23-ene derivative; And 24-hydrop-25-ene derivative.
Hydrophilic ginsenoside's chemical compound is in above-mentioned absorption process, the saponin compound of original shape is hydrolyzed, decomposition, metabolism are secondary metabolite or final metabolite is absorbed, thereby make saponin compound not give full play to its biological activity and pharmacologically active, reduced its due medical value with original shape.
Medicinal or nutrition in the natural plants also has quite a few alkaloid and flavone compound with active component, also all has medical value widely, be used to prepare medicine and the health food or the health product for the treatment of various diseases, as soybean isoflavone, genistein, bilobalide, propolis etc.These medicines or nutrient can be divided into above-mentioned two big classes: hydrophilic and lipophilic medicine.The bottleneck problem that above-mentioned saponins medicine runs into when absorbing also can appear in the oral absorption dosage form of these medicines.
Be subjected to the gastro-intestinal Fluid environmental effect for fear of the biological and pharmacological action by gastrointestinal tract time of medicine or nutrient, pharmaceutical field has carried out research extensively and profoundly to this at present, how research controls medicine not disintegrate by stomach the time, the control medicine enters into the intestinal position and begins disintegrate, release, is absorbed.By designing not by dissolved encrusting substance of gastric juice or wrappage, can be when making medicine or nutraceutical active component by disintegrate or release through stomach, but delay to discharge to the intestinal position, the specific blood drug level and the bioavailability of medicament that obtain to expect are in the hope of reaching better therapeutic effect.Yet, even can arriving the intestinal position by gastric juice smoothly, medicine or nutrient begin disintegrate, release, or the degraded of process stomach position also has the remainder medicine to arrive the small intestinal position, because the influence of intestinal environment (pH value, enzyme, bacterium etc.), add the physicochemical property of most drug active component own, its absorbance and bioavailability still can be a greater impact.
Therefore; from practical standpoint; exist a kind of urgent needs; protection original shape medicine or nutrient at gastrointestinal tract not by gastrointestinal tract environment (acid; enzyme and bacterium) decompose and destroy; and in gastroenteric environment, do not separate out; keep dissolved molecularity; make medicine or nutrient in stomach, to be absorbed in a large number; dwindle the assimilation ratio of medicine at the intestinal position; reduce or avoid influencing the various factors of medicine or nutrient absorption; can make simultaneously medicine or nutrient with the original shape state but not metabolite in stomach and intestinal effectively absorbed, thereby increase medicine or nutraceutical overall absorption rate and bioavailability.
Invention is described
The objective of the invention is above-mentioned deficiency at prior art; a kind of method and prescription that changes oral drugs or nutraceutical absorption approach and improve whole bioavailability proposed; make medicine or nutrient before being absorbed, be protected and be not subjected to the influence and the decomposition of gastroenteric environment liquid; the molecularity that can hold its shape medicine or nutraceutical dissolved state and be convenient to absorb; make medicine or nutrient in stomach, to be absorbed in a large number; dwindle medicine or nutrient assimilation ratio, reduce or avoid influencing the various factors of drug absorption at the intestinal position.This method makes and to contain treatment effective dose of medicine thing or nutrient is keeping its physical and chemical stability with gastric juice, intestinal absorption environment when contacting, promptly not by the decomposition of gastric juice and intestinal environment, destruction with in gastrointestinal tract, do not separate out, can mainly in stomach, be absorbed in a large number simultaneously, change the most of tradition of intestinal absorption that relies on of oral drugs or nutrient and absorb approach, greatly improve whole original shape absorbance of oral drugs or nutrient and bioavailability.
Method and composition prescription provided by the invention not only can be applied to the preparation of the oral formulations of medicinal or water soluble compound that nutrition is used and fat-soluble compound, and more particularly can be applied to comprise the preparation of the medicinal or nutrition of water soluble compound and fat-soluble compound with the oral formulations of mixture.Make this mixture oral formulations with gastric juice, when the intestinal absorption environment contacts not by the decomposition of gastric juice and intestinal environment, destruction with in gastrointestinal tract, do not separate out, can mainly in stomach, be absorbed in a large number simultaneously, change the most of tradition of intestinal absorption that relies on of oral drugs or nutrient and absorb approach, greatly improve oral drugs overall absorption and bioavailability.
In order to realize purpose of the present invention, method of the present invention is by a kind of special organic solvent composite formula is provided, water soluble compound, fat-soluble compound or both mixture medicinal or that nutrition is used are prepared from oral formulations, use the oral formulations of the inventive method preparation, can tolerate the influence of acid, water, enzyme and bacterium in the gastrointestinal tract environment, not be decomposed and separate out.This prescription can make medicine be absorbed by the body with original shape medicine rather than metabolite, and mainly in stomach, absorbed in a large number, thereby reach greatly improve medicinal or nutrition with the overall absorption rate of chemical compound or mixture and the purpose of bioavailability, medicine or nutraceutical biological activity and pharmacologically active are achieved.
The composite formula of organic solvent provided by the invention be with medicinal or chemical compound that nutrition is used or mixture be that medicinal or nutrition is comprised that with material monomeric compound and mixture mix with in the following organic solvent one or more by being selected from following its concrete grammar and composite formula.This class organic solvent includes but not limited to fish oil, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils; And ethanol; propylene glycol; glycerol; Polyethylene Glycol; ethyl acetate; the mixing of one or more of organic solvents such as propylene carbonate; also be selected from following one or more antiacid protective agents and mix: the antiacid protective agent of this class includes but not limited to following compounds; as: Labrafil M 1944CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); CremophorRH40; polyoxyethylene-fatty acid esters of sorbitan (polyoxyethylene sorbitan monolaurate for example; polysorbas20); Nikkol HCO40; Nikkol HCO 50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; the mixing of one or more of glyceryl monostearate, the special medicine or the nutraceutical organic solvent prescription of containing of composition.After this prescription prepares, can make medicinal or dosage form that nutrition is used commonly used again, such as oral liquid, liquid capsule, soft capsule etc.
The composite formula of preferable methods that provides of the present invention and organic solvent is medicinal or water soluble compound, fat-soluble compound or both mixture that nutrition is used are mixed with polyoxyethylene product (polyoxyethylene hydrogenated Oleum Ricini, Cremophor RH40) by the hydrogenated vegetable oil of the ethanol of different purity and different proportion and to make, make after the combinations thereof composition formula with said method, again composite formula is made known oral formulations (including but not limited to oral liquid, soft capsule, duricrust liquid capsule and other known peroral dosage forms).Above-mentioned prescription contains the medicine or the nutrient of dose therapeutically effective, and at least with polyoxyethylene product (polyoxyethylene hydrogenated Oleum Ricini, the Cremophor RH40) compatibility of ethanol and hydrogenated vegetable oil, also can add other pharmaceutically acceptable pharmaceutical carrier or adjuvants, comprise bulking agent, surfactant, food additive etc.
The inventive method has following characteristics and innovation:
1. utilization contains the polyoxyethylene hydrogenated Oleum Ricini (or above-mentioned other antiacid protective agents) of the ethanol (or above-mentioned other organic solvents) of different purity and different proportion as medicine or nutraceutical special organic assembling composition formula, protect dissolved drug solution (acid, enzyme, bacterium) and intestinal environment (acid, enzyme, bacterium) under the gastric juice environment not to be decomposed or metabolism, or do not separated out by crystallization;
2. the organic solvent of this specific combination composition formula not only can dissolve biologically active amphipathic aqueous and lipophilic chemical compound, can also dissolve hydrophilic and lipophilic mixture.
3. specific combination composition formula of the present invention is characterised in that and can makes that effective ingredient mainly is absorbed in stomach, and the main absorption site of medicine is at intestinal traditionally, so the present invention has changed traditional absorption site of oral drugs.
4. can reduce active component and in gastrointestinal tract, be degraded or metabolism, thereby keep original shape medicine original biological activity and pharmacologically active, and can avoid the issuable ill effect of secondary metabolite.
The method disclosed in the present may further comprise the steps:
The first step: determine medicine or the nutrient dissolubility in organic solvent.The definite of dissolubility can be undertaken by experimental technique well known in the art, or finds from document.In dissolubility, determine the formula proportion of medicine or nutrient and organic solvent then.
Second step:
(1), medicine or nutrient are dissolved in the organic solvent of different purity fully, and organic solvent is selected from one or more mixing of following organic solvent: fish oil, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils, ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethyl acetate, propylene carbonate; Obtain after the dissolving " intermediate solution A "
(2), definite protectant ratio of solution that in " intermediate solution A ", should add.The solution protective agent is one or more mixing that are selected from following: Labrafil M 1944CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); Cremophor RH40; polyoxyethylene-fatty acid esters of sorbitan (for example polyoxyethylene sorbitan monolaurate, polysorbas20); Nikkol HC040; Nikkol HCO 50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; glyceryl monostearate etc.Again by experimental technique well known in the art; simulate simulated gastric fluid and simulated intestinal fluid in advance; contain with above-mentioned that medicine or nutraceutical specific combination composition formula are put into mimic artificial gastric juice and intestinal juice carries out the experiment of stability; dissolve fully at simulated gastric fluid and intestinal juice environment according to drug solution; stable and non-crystallizable separating out is standard, the protectant ratio of solution when obtaining respectively not separate out in gastric juice and intestinal juice.Medicine that so obtains or nutrient and above-mentioned organic solvent and above-mentioned solvent protective agent ratio each other are exactly specific combination composition formula disclosed in this invention.
The 3rd step: contain medicine or nutraceutical composite formula according to what abovementioned steps obtained, be prepared into known oral formulations according to pharmacy and food service industry production standard again, such as oral liquid, soft capsule, liquid capsule etc., also can also add flavoring agent or other edible pharmaceutic adjuvant or edible additive as required.
The ratio of composite formula provided by the invention is:
(1) medicine or nutraceutical content are 5%--90% (weight, down together), and preferred version is 10%--50%;
(2) one or more the blended content as the fish oil of organic solvent, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils, ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethyl acetate, propylene carbonate is 5%--90%, and preferred version is 5%--50%;
(3) as the protectant Labrafil M of drug solution 1944CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); Cremophor RH40; polyoxyethylene-fatty acid esters of sorbitan (polyoxyethylene sorbitan monolaurate for example; polysorbas20); Nikkol HCO40; Nikkol HCO 50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; the blended content of one or more of glyceryl monostearate etc. is 5%--90%, and preferred version is 12.5%--60%.
Specific combination composition formula provided by the invention is most preferably filled a prescription and ratio is:
(1) medicament contg is 5%--90% (weight, down together), and preferred version is 10%--50%;
(2) ethanol is 5%--90% as the content of organic solvent, and preferred version is 5%--50%;
(3) polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 is 5%--90% as the protectant content of drug solution, and preferred version is 12.5%--60%.
Method of the present invention and and composite formula can be applied to the preparation of the oral medicine, nutrient, health-oriented products, health food or the functional food that contain biologically active amphipathic aqueous chemical compound, lipophilic compound and both mixture.
The final dosage form of the method disclosed in the present and composite formula comprises oral liquid, oral soft capsule, oral duricrust liquid capsule or other known dosage form, contains composite formula disclosed in this invention in these dosage forms in the effective ingredient.
Described medicine of the present invention or nutrient are meant bioactive lipophilic compounds, hydrophilic compounds and both mixture medicines or nutrient; Preferred component is selected from Coumarins, triterpene saponin or aglycon class, steroid saponin, flavonoid, the diterpene that obtains from natural product, sesquiterpenoids lactone or quinones include but not limited to the medicine of following kind: ginsenoside Rh2, Rg3, protopanoxadiol aglycon, Protopanaxatriol's aglycon, Radix Ginseng total saponins, Radix Astragali saponin, platycodin, saikoside, dioscin, baicalin, puerarin, genistein, soybean isoflavone, bilobalide, bilobalide, propolis, psoralen, imperatorin, TANSHINONES etc.
Method of the present invention can also add other known and pharmaceutically acceptable pharmaceutical carrier or adjuvants, as sweeting agent, solubilizing agent, surfactant etc., but does not constitute necessary component of the present invention.
The application of the inventive method, can be according to the different medical values of bioactive lipophilic and hydrophilic medicament, be prepared into oral formulations, be applied to include but not limited to following antiulcer, pain relieving, resisting hypertension, anti-cardiovascular disease, the preparation of antibiotic, psychosis, antitumor, anti-muscarine, diuretic, migraine, antiviral, antiinflammatory, tranquilizer, anti-diabetic, endocrine regulation, defying age, antidepressant, hydryllin, anti-parasitic, epilepsy disease, lipotropism medicine etc.
Description of drawings
Blood drug level after Fig. 1, ginsenoside Rg3 take in different dosage form is curve over time.
Fig. 2, protopanoxadiol aglycon aPPD be the blood drug level curve over time after the oral and injection in different dosage form
Implementation example
Below in conjunction with drawings and Examples the present invention is further described, does not constitute any restriction scope of the present invention in this implementation example.
Embodiment one, biologically active amphipathic aqueous and lipophilic drugs are at the assay method of dissolve with ethanol degree:
In Chinese Pharmacopoeia 2000 editions, the dissolubility of having stipulated medicine is divided into very easily dissolving, Yi Rong, dissolving, slightly molten, slightly soluble, soluble,very slightly, 7 ranks such as insoluble or insoluble almost.Require as follows accordingly:
Very easily dissolving means that solute 1g (ml) can dissolve in less than 1ml at solvent;
Yi Rong means that solute 1g (ml) can dissolve in less than 10ml at solvent 1-;
Dissolving means that solute 1g (ml) can dissolve in less than 30ml at solvent 10-;
The slightly molten solute 1g (ml) that means can dissolve in less than 100ml at solvent 30-;
Slightly soluble means that solute 1g (ml) can dissolve in less than 1000ml at solvent 100-;
Soluble,very slightly means that solute 1g (ml) can dissolve in less than 10000ml at solvent 1000-;
The almost insoluble or insoluble solute 1g (ml) that means can not dissolve in solvent 10000ml fully.
Also stipulated the solubility test method of standard in 2000 editions two notes on the use of Chinese Pharmacopoeia:
Take by weighing the test sample that is ground into fine powder or measure the liquid test sample, place the solvent of 25 ℃ ± 2 ℃ of certain molten amounts, powerful jolting was 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, as when cannot see particles of solute or drop, even dissolving fully.
The method of embodiment two, simulation simulated gastric fluid environment and artificial intestinal environment:
Method according to " capsule " it " note " defined in " pharmaceutical preparation general rule " prepares simulated gastric fluid and simulated intestinal fluid:
1. simulated gastric fluid: get dilute hydrochloric acid 16.4ml, add about 800ml of water and pepsin 10g, after shaking up, add the water weighing apparatus and release to 1000ml, promptly.
2. simulated intestinal fluid: get potassium dihydrogen phosphate 6.8g, add water 500ml and make dissolving, regulate pH value to 6.8 with 0.4% sodium hydroxide solution and get pancreatin 10g in addition, amount of water makes dissolving, after two liquid are mixed, thin up to 1000ml promptly.
The method of the oral formulations of the glycosides compound medicine of embodiment three, preparation biologically active amphipathic aqueous.
1, the ginsenoside Rg3 is dissolved in ethanol:
Take by weighing 100 milligrams of ginsenoside Rg3's test samples of Different Weight, place 90% the alcoholic solution of 25 ℃ ± 2 ℃ of 100ml respectively, powerful jolting was 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, fully dissolving.
2, the alcohol solvent of configuration medicine:
According to containing of above acquisition of effective dosage ginsenoside Rg3's alcoholic solution 100ml, use for the ratio of determining polyoxyethylene hydrogenated Oleum Ricini.
3, set up simulation simulated gastric fluid environment and intestinal environment:
Method according to embodiment two prepares simulated gastric fluid and simulated intestinal fluid.
4, determine to contain the ratio of protective agent polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 in ginsenoside Rg3's the drug solution:
The polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 that adds the 5%-90% ratio respectively is in ginsenoside Rg3's alcoholic solution 100ml that the foundation above-mentioned steps obtains, the medicine alcoholic solution is put into mimic artificial gastric juice and simulated intestinal fluid is tested, with medicine be not hydrolyzed, not by metabolism with not separate out be standard, obtain the ratio data in simulated gastric fluid and intestinal juice respectively, high person is as the criterion with the ratio among both, as allocation ratio, be defined as 50%, 175mg;
5,, and prepare ginsenoside Rg3's various oral formulations according to the general character Codes and Standards of pharmaceutical industry and food service industry according to the ratio of above acquisition.
The method of the oral formulations of the glycosides compound medicine of embodiment four, preparation bioactive lipophilic.
1, protopanoxadiol sapogenin aPPD dissolves in ethanol:
Take by weighing 40 milligrams of the protopanoxadiol sapogenin aPPD test samples of Different Weight, place 90% the alcoholic solution of 25 ℃ ± 2 ℃ of 100ml respectively, powerful jolting was 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, fully dissolving.
2, the alcohol solvent of configuration medicine:
Configuration contains the alcoholic solution 100ml of the protopanoxadiol sapogenin aPPD of effective dosage according to the dissolubility of above acquisition, for the ratio use of determining polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40.
3, set up simulation simulated gastric fluid environment and intestinal environment:
Method according to embodiment two prepares simulated gastric fluid and simulated intestinal fluid.
4, determine to contain the ratio of protective agent polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 in the drug solution of protopanoxadiol sapogenin aPPD:
The polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 that adds the 5%-90% ratio respectively is in the alcoholic solution 100ml of the protopanoxadiol sapogenin aPPD that the foundation above-mentioned steps obtains, the medicine alcoholic solution is put into mimic artificial gastric juice and simulated intestinal fluid is tested, with medicine be not hydrolyzed, not by metabolism with not separate out be standard, obtain the ratio data in simulated gastric fluid and intestinal juice respectively, high person is as the criterion with the ratio among both, as allocation ratio, obtain 40%, 150mg;
5, prepare the various oral formulations of protopanoxadiol sapogenin aPPD according to the aforementioned proportion that obtains, and according to the general character Codes and Standards of pharmaceutical industry and food service industry.
The method of the oral formulations of embodiment five, the preparation lipophilic glycosides of hydrophilic and aglycon class mixture medicines
1, glycosides and aglycon class mixture medicines dissolve in ethanol:
Take by weighing 150 milligrams of the glycosides of Different Weight and aglycon class mixture medicines test samples, place 90% the alcoholic solution of 25 ℃ ± 2 ℃ of 100ml respectively, powerful jolting was 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, fully dissolving.
2, the alcohol solvent of configuration medicine:
Dissolubility configuration according to above acquisition contains the glycosides of effective dosage and the alcoholic solution 100ml of aglycon class mixture, uses for the ratio of determining polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40.
3, set up simulation simulated gastric fluid environment and intestinal environment:
Method according to embodiment two prepares simulated gastric fluid and simulated intestinal fluid.
4, determine the ratio of protective agent polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 in the drug solution of glycosides and aglycon class mixture:
The polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 that adds the 5%-90% ratio respectively is in the alcoholic solution 100ml of glycosides that the foundation above-mentioned steps obtains and aglycon class mixture, the medicine alcoholic solution is put into mimic artificial gastric juice and simulated intestinal fluid is tested, with medicine be not hydrolyzed, not by metabolism with not separate out be standard, obtain the ratio data in simulated gastric fluid and intestinal juice respectively, high person is as the criterion with the ratio among both, as allocation ratio, the acquisition ratio is 37%, 150mg;
5, prepare glycosides and the various oral formulations of aglycon class mixture according to the aforementioned proportion that obtains, and according to the general character Codes and Standards of pharmaceutical industry and food service industry.
The oral formulations of the ginsengenin chemical compound health product of embodiment six, preparation bioactive lipophilic
1. take by weighing protopanoxadiol sapogenin aPPD 100mg, ethanol 120mg, aPPD inserts in the ethanol with the protopanoxadiol sapogenin, stirs until whole dissolvings;
2. take by weighing 175mg castor oil hydrogenated Cremophor 40, insert in the vacuum emulsification blender, be preheated to 35 ℃, the alcoholic solution with above-mentioned protopanoxadiol sapogenin aPPD adds again, mixes liquid and stirs evenly until dissolving fully, is as clear as crystal state;
3. the medicament mixed liquid of above-mentioned mix homogeneously is inserted homogenizer and carry out froth breaking, the mixed liquor of finishing froth breaking is put into clean container;
4. above-mentioned oral liquid solution is carried out fill according to the current standard of pharmaceutical industry, comprise and carry out quality examination control, sanitary standard etc.
Embodiment seven, saponins and the experiment of aglycon class drug bioavailability
The bioavailability of specific combination composition formula disclosed in this invention and the bioavailability of general formulation are compared, can greatly improve the bioavailability of oral drugs in order to proof the present invention:
1, test of the human body blood drug level of ginsenoside Rg3's medicine and bioavailability test:
(1) human body blood drug level test test method:
(a) subjects: 6 strong male's volunteers of (40-45) body of growing up;
(b) make with medicament: ginsenoside Rg3 prepared according to the methods of the invention makes the specific combination composition formula, and its formula proportion is: the ginsenoside Rg3: 100 milligrams, and dehydrated alcohol: 75 milligrams, polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40:175 milligram.Again this specific combination composition formula is made soft capsule by known method.Ginsenoside Rg3's common duricrust powder capsule is commercial two kinds of dosage forms of " joining a capsule " Rg3 that obtain on market;
(c) using dosage: be the medication of 300mg single;
(d) interval of taking a blood sample: after medication, took a blood sample respectively in the 30th, 60,120,180,240 and 300 minute;
(e) behind the individual blood drug level that obtains, average, obtain following result.
(2) blood drug level test result: (see figure 1)
(3) relative bioavailability relatively
Time/minute Blood drug level (ng/ml)
The Rg3 oral soft capsule The Rg3 hard capsule
0
5
30 345±31 21±7
60 745±65 27±11
120 349.5±32 15±5
180 236.25±19 11±4
240 159.75±20 9±3
300 107.625±17 8±1
Preparation Bioavailability parameter (AUC) Bioavailability is (%) relatively
A UC 0-24/ng.h/ml
The Rg3 oral soft capsule 1989.37 1722％
The Rg3 hard capsule 115.5 1
2, test of the human body blood drug level of protopanoxadiol aglycon medicine and bioavailability test:
The former Radix Ginseng soap glycol oral soft capsule prepared according to the methods of the invention and the intravenous fluid (IV) of protopanoxadiol aglycon and carry out bioavailability relatively according to three kinds of dosage forms of common duricrust powder capsule of usual method preparation prove that the present invention can greatly improve the bioavailability of oral drugs:
(1) human body blood drug level test method is as follows:
(a) subjects: 12 strong male's volunteers of (40-45) body of growing up;
(b) make with medicament:
(i) soft capsule: the specific combination composition formula of protopanoxadiol aglycon aPPD prepared according to the methods of the invention, its formula proportion is: protopanoxadiol aglycon aPPD:100 milligram, dehydrated alcohol: 120 milligrams, polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40:150 milligram.Again this specific combination composition formula is made soft capsule by known method;
(ii) intravenous fluid: the intravenous fluid that contains the protopanoxadiol aglycon prepared according to the methods of the invention;
(iii) duricrust powder capsule: according to the duricrust powder capsule that contains the protopanoxadiol aglycon of common known method preparation;
(c) using dosage: be the medication of 800mg single;
(d) take a blood sample clock, 60 fens interbody spacers: the blood sampling of intravenous fluid is to finish in instillation at instil (IV) to get blood for the first time in preceding 5 minutes, takes a blood sample respectively at 30 minutes, 120 minutes, 180 minutes, 240 minutes; Other three kinds of peroral dosage forms were taken a blood sample respectively after medication on the the 30th, 60,120,180,240 and 300 minute;
(e) average behind the individual blood drug level that obtains, the blood drug level test result as shown in Figure 2.
(2) the absolute bioavailability comparative result is as shown in the table:
Time/minute Blood drug level (ng/ml)
Intravenous fluid Oral soft capsule Oral liquid Oral hard capsule
0
5 8206±425
30 1928±234 920±87 820±79 17±20
60 1266±137 1987±201 578±64 11±20
120 725±93 932±83 470±57
180 534±39 630±57 210±19
240 408±5l 426±53 125±20
300 281±19 287±20 83±13
Preparation Bioavailability parameter (AUC) Bioavailability is (%) relatively
AUC 0-24/ng.h/ml
Intravenous fluid (IV) 6451 1
Oral soft capsule 5305 82.2％
Oral liquid 2580 40.1％
Oral hard capsule - ＜1％
Above-mentioned experiment shows that the bioavailability of the ginsenoside Rg3 of the biologically active amphipathic aqueous of employing the present invention preparation and the protopanoxadiol aglycon soft capsule of bioactive lipophilic and oral liquid is much higher than the duricrust powder capsule of traditional preparation process method preparation.The hard capsule of traditional preparation process method preparation owing to be subjected to the influence of gastrointestinal absorption environment and the physicochemical property of medicine itself, be decomposed easily in gastro-intestinal Fluid or separate out or decomposition etc., and it is poor to make in gastrointestinal absorption.Because the present invention has used the protective agent that dissolving back medicine is not decomposed by gastro-intestinal Fluid, makes drug solution still can keep molecularity in gastro-intestinal Fluid; Simultaneously owing to use ethanol as the carrier that absorbs by gastrointestinal, make medicine be absorbed by gastrointestinal tract together in the absorbed while of ethanol, if changed the logical product glycosides of medicine or the absorption channel of aglycon class drug main process intestinal absorption, greatly improved bioavailability of medicament.

Claims (25)

1, a kind of medicine or nutraceutical composite formula is characterized in that: medicine or nutrient with at least by organic solvent and can make the physicochemical property of effective ingredient avoid the formulated organic solution of the destructive protective agent of gastrointestinal tract environment to mix.
2, composite formula according to claim 1, wherein organic solvent is selected from one or more mixing of fish oil, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils, ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethyl acetate, propylene carbonate.
3; composite formula according to claim 1; the protective agent of its Chinese medicine is selected from Labrafil M 1944CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); Cremophor RH40; polyoxyethylene-fatty acid esters of sorbitan (for example polyoxyethylene sorbitan monolaurate, polysorbas20); Nikkol HCO40; Nikkol HCO 50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; one or more mixing of glyceryl monostearate.
4, composite formula according to claim 1, the antiacid protective agent of organic solvent medicine wherein can be the polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 of the polyoxyethylene product of hydrogenated vegetable oil.
5, composite formula according to claim 4, concrete proportioning wherein is: medicine or nutrient inventory are 5%--90% (weight, down together), and preferred version is 10%--50%; Ethanol content is 5%--90%, and preferred version is 5%--50%; The content of polyoxyethylene hydrogenated Oleum Ricini Cremophor RH40 is 5%--90%, and preferred version is 12.5%--60%.
6,, its role is to make medicine or nutrient composition in the prescription to enter blood with the original shape absorption according to the described composite formula of claim 1 to 5.
7, according to the described composite formula of claim 1 to 5, its role is to change absorption site in the body of medicine in the prescription or nutrient composition, increase gastric and absorb.
8,, its role is to make the medicine in the prescription or the oral absorption rate and the bioavailability of nutrient composition to be improved according to the described composite formula of claim 1 to 5.
9, made medicine or the nutraceutical preparation of a kind of combination formula according to claim 1 is characterized in that: medicine or nutrient and at least by the formulated mixed solution of the antiacid protective agent of organic solvent and medicine.
10, medicine according to claim 9 or nutrient preparation, wherein said medicine or nutrient composition can be hydrophilic compounds, lipophilic compound and both mixture.
11, medicine according to claim 9 or nutrient preparation, wherein said medicine or nutrient composition can be selected from one or more mixing in the following chemical compound: Coumarins, triterpene saponin or aglycon class, steroid saponin, flavonoid, diterpene, sesquiterpenoids lactone or quinones comprise the ginsenoside Rh2, Rg3, the protopanoxadiol aglycon, Protopanaxatriol's aglycon, Radix Ginseng total saponins, Radix Astragali saponin, platycodin, saikoside, dioscin, baicalin, puerarin, genistein, soybean isoflavone, bilobalide, bilobalide, propolis, psoralen, imperatorin, TANSHINONES etc.
12, medicine according to claim 9 or nutrient preparation, wherein said medicine or nutrient composition can be selected from one or more mixing in the following chemical compound: triterpene saponin or aglycon class, steroid saponin comprise ginsenoside Rh2, Rg3, protopanoxadiol aglycon, Protopanaxatriol's aglycon, Radix Ginseng total saponins, Radix Astragali saponin, platycodin, saikoside, dioscin, baicalin.
13, medicine according to claim 9 or nutrient preparation, wherein said medicine or nutrient composition can be selected from one or more mixing in the following chemical compound: ginsenoside Rh2, Rg3, protopanoxadiol aglycon, Protopanaxatriol's aglycon, various other ginsenosides, Radix Ginseng total saponins.
14, medicine according to claim 9 or nutrient preparation, wherein said medicine or nutrient composition can be selected from one or more mixing in the following chemical compound: Radix Astragali saponin, platycodin, saikoside, dioscin, baicalin.
15, medicine according to claim 9 or nutrient preparation, wherein organic solvent is selected from one or more mixing of fish oil, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils, ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethyl acetate, propylene carbonate.
16; medicine according to claim 9 or nutrient preparation; the antiacid protective agent of its Chinese medicine is selected from Labrafil M 1944 CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); Cremophor RH40; polyoxyethylene-fatty acid esters of sorbitan (for example polyoxyethylene sorbitan monolaurate, polysorbas20); Nikkol HCO40; Nikkol HCO50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; one or more mixing of glyceryl monostearate.
17, medicine according to claim 9 or nutrient preparation, the antiacid protective agent of organic solvent medicine wherein can be the polyoxyethylene products (polyoxyethylene hydrogenated Oleum Ricini) of hydrogenated vegetable oil.
18, medicine according to claim 9 or nutrient preparation, concrete proportioning wherein is: medicine or nutrient inventory are 5%--90% (weight, down together), and preferred version is 10%--50%; Ethanol content is 5%--90%, and preferred version is 5%--50%; The content of polyoxyethylene hydrogenated Oleum Ricini is 5%--90%, and preferred version is 12.5%--60%.
19,, its role is to make medicine or nutrient composition in the preparation to enter blood with the original shape absorption according to described medicine of claim 9 to 18 or nutrient preparation.
20, according to described medicine of claim 9 to 18 or nutrient preparation, its role is to change absorption site in the body of medicine in the preparation or nutrient composition, increase gastric and absorb.
21,, its role is to make the medicine in the preparation or the oral absorption rate and the bioavailability of nutrient composition to be improved according to described medicine of claim 9 to 18 or nutrient preparation.
22, according to claim 1 or 18 described composite formulas and medicine or nutrient preparation, the form of its final peroral dosage form can be oral liquid, oral soft capsule, oral duricrust liquid capsule and other known medicines or nutraceutical dosage form.
23, a kind of medicine that promotes absorbs and improves the method for whole bioavailability at stomach, it is characterized in that: medicine or nutrient are dissolved in the oral formulations of making medicine in the organic solvent of special formulation, main absorbent portion is changed into stomach by traditional at the intestinal position, the dissolved state of medicine holds its shape, make the prototype medicine but not metabolite is directly absorbed, thereby help improving the whole original shape bioavailability of medicine.It specifically may further comprise the steps:
The first step: determine medicine or the nutrient dissolubility in organic solvent.The definite of dissolubility can be undertaken by experimental technique well known in the art, or finds from document.In dissolubility, determine the formula proportion of medicine or nutrient and organic solvent then.
Second step:
(1), medicine or nutrient are dissolved in the organic solvent of different purity fully, and organic solvent is selected from one or more mixing of following organic solvent: fish oil, safflower oil, refined soybean oil, refining Oleum Arachidis hypogaeae semen, Radix Oenotherae erythrosepalae oil, Herba Silybi mariani oil, Oleum Vitis viniferae, Oleum Helianthi, Fructus Hippophae wet goods vegetable and animals oils, ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethyl acetate, propylene carbonate; Obtain after the dissolving " intermediate solution A "
(2), definite protectant ratio of solution that in " intermediate solution A ", should add.The solution protective agent is one or more mixing that are selected from following: Labrafil M 1944 CS; polysorbas20; tween 21; polysorbate40; polysorbate60; Tween 80; sorbimacrogol oleate100; Brij; Spans (also claiming fatty acid esters of sorbitan); Macrogol 200-Macrogol 600; soybean phospholipid; lecithin; polyglycerin ester; sucrose ester; the polyoxyethylene product of hydrogenated vegetable oil (for example polyoxyethylene hydrogenated Oleum Ricini); Cremophor RH40; polyoxyethylene-fatty acid esters of sorbitan (for example polyoxyethylene sorbitan monolaurate, polysorbas20); Nikkol HCO 40; Nikkol HCO 50; Nikkol HCO 60; sodium lauryl sulphate; Stepanol MG; dodecyl sodium sulfate; sodium tetradecyl sulfate; glyceryl monostearate.Again by experimental technique well known in the art; simulate simulated gastric fluid and simulated intestinal fluid in advance; contain with above-mentioned that medicine or nutraceutical specific combination composition formula are put into mimic artificial gastric juice and intestinal juice carries out the experiment of stability; dissolve fully at simulated gastric fluid and intestinal juice environment according to drug solution; stable and non-crystallizable separating out is standard, the protectant ratio of solution when obtaining respectively not separate out in gastric juice and intestinal juice.Medicine that so obtains or nutrient and above-mentioned organic solvent and above-mentioned solvent protective agent ratio each other are exactly specific combination composition formula disclosed in this invention.
The 3rd step: contain medicine or nutraceutical composite formula according to what abovementioned steps obtained, be prepared into known oral formulations according to pharmacy and food service industry production standard again, such as oral liquid, soft capsule, liquid capsule etc., also can also add flavoring agent or other edible pharmaceutic adjuvant or edible additive as required.
24, according to claim 23, method of the present invention can be applied to the preparation of the oral formulations of medicine, health-oriented products, nutrition product or functional food.
25, according to claim 23, method of the present invention can be applied to but be not limited to the preparation of the oral formulations of antiulcer, pain relieving, resisting hypertension, anti-cardiovascular disease, antibiotic, psychosis, antineoplastic agent, anti-muscarine, diuretic, migraine, antiviral, antiinflammatory, tranquilizer, endocrine regulation, antidiabetic, antidepressant, hydryllin, anti-parasitic, epilepsy disease, lipotropism medicine etc., and the preparation of health-oriented products preparation such as health product, nutriment, health food, functional food.
CNA2005100671261A 2005-04-19 2005-04-19 Method prescription and use for improving medicine or nutrient oral absorption Pending CN1853728A (en)

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CNA2005100671261A CN1853728A (en) 2005-04-19 2005-04-19 Method prescription and use for improving medicine or nutrient oral absorption
JP2008506904A JP2008536879A (en) 2005-04-19 2006-04-19 Drug or nutrition combination preparation and preparation, method for improving absorption by internal use, and application method thereof
EP06722367A EP1878445A4 (en) 2005-04-19 2006-04-19 A method, formulation and use thereor with improved oral absorption of drugs or nutrients
PCT/CN2006/000718 WO2006111085A1 (en) 2005-04-19 2006-04-19 A method, formulation and use thereor with improved oral absorption of drugs or nutrients
US11/875,047 US20080038335A1 (en) 2005-04-19 2007-10-19 Method, formulation, and use thereof for improved oral absorption of pharmaceuticals or nutrients

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CN113475650A (en) * 2021-07-06 2021-10-08 上海百润投资控股集团股份有限公司 Grape essence

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CN103249403B (en) * 2010-09-22 2016-01-27 克劳研究有限公司 Pharmaceutical composition of poon element and the plain derivant of poon and analog and preparation method thereof
CN111789943A (en) * 2019-04-08 2020-10-20 洛阳赛威生物科技有限公司 Oil-in-water adjuvant composition and preparation method and application thereof
CN111789943B (en) * 2019-04-08 2024-01-19 洛阳赛威生物科技有限公司 Oil-in-water adjuvant composition and preparation method and application thereof
CN113475650A (en) * 2021-07-06 2021-10-08 上海百润投资控股集团股份有限公司 Grape essence

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JP2008536879A (en) 2008-09-11
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WO2006111085A1 (en) 2006-10-26
EP1878445A1 (en) 2008-01-16

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